UCSF

Aging is defined by a progressive deterioration of tissue and organ functionality during adulthood. Across species from invertebrates to mammals, the female reproductive system has consistently been found to be one of the first organs to lose functionality with age. While oocytes have long been assumed to be the primary cells affected by aging, growing evidence points to ovarian somatic cells as key contributors, though the molecular mechanisms driving their aging remain poorly understood. In the Drosophila ovary, a layer of somatic follicle cells surrounds each germ-cell cyst. These follicle cells are essential for guiding and supporting germ-cell cyst development into a mature oocyte. We found that aging is characterized by an accumulation of phenotypes in the somatic compartment, including failure of the follicle cells to encapsulate germ-cell cysts, an extended S phase, and increased DNA damage. These follicle encapsulation defects are associated with the lack of a germ-cell cyst checkpoint in early oogenesis. Single-cell RNA sequencing revealed that, across all cell types in the ovary, cells in the follicle lineage have the highest number of differentially expressed genes. Overexpression of Atg8a, a key autophagy machinery gene homologous to mammalian LC3, specifically in follicle cells prevents age-associated decline in the follicle epithelium and loss of reproductive capacity. Collectively, these findings demonstrate that genetic manipulation of a small population of ovarian somatic cells is sufficient to improve both cell-autonomous and non-autonomous features of reproductive aging.